Vol 92, No 1 (2021)
Review paper
Published online: 2020-12-30

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Prenatal diagnosis of glutaric acidemia type 2 with the use of exome sequencing — an up-to-date review and new case report

Anna M. Kucinska-Chahwan1, Tomasz Roszkowski1, Maciej Geremek2, Magdalena A. Paczkowska2, Michal Ciebiera3, Julia Bijok1, Diana Massalska1, Grzegorz Panek1, Krzysztof Siemion4, Beata A. Nowakowska2
Pubmed: 33448012
Ginekol Pol 2021;92(1):51-56.


Introduction: Inborn errors of metabolism (IEM) also called metabolic diseases constitute a large and heterogenous group of disorders characterized by a failure of essential cellular functions. Antenatal manifestation of IEM is absent or nonspecific, which makes prenatal diagnosis challenging. Glutaric acidemia type 2 (GA2) is a rare metabolic disease clinically manifested in three different ways: neonatal-onset with congenital anomalies, neonatal-onset without congenital anomalies and late-onset. Neonatal forms are usually lethal. Congenital anomalies present on prenatal ultrasound as large, hyperechoic or cystic kidneys with reduced amniotic fluid volume. Material and methods: We present a systematic literature review describing prenatal diagnosis of GA2 and a new prenatal case. Results: Ten prenatally diagnosed cases of GA2 have been published to date, mainly based on biochemical methods. New case of GA2 was diagnosed using exome sequencing method. Discussion: All prenatal cases from literature review had positive history of GA2 running in the family. In our study trio exome sequencing was performed in case of fetal hyperechoic kidneys without a history of GA2. Consequently, we were able to identify two novel pathogenic variants of the ETFDH gene and to indicate their parental origin. Summary: Exome sequencing approach used in case of fetal hyperechoic kidneys allows to identify pathogenic variants without earlier knowledge of the precise genetic background of the disease. Hyperechoic, enlarged kidneys could be one of the clinical features of metabolic diseases. After exclusion of chromosomal abnormalities, urinary tract obstruction and intrauterine infections, glutaric acidemia type 2 and number of monogenic disorders should be consider.

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  1. Arnold GL. Inborn errors of metabolism in the 21 century: past to present. Ann Transl Med. 2018; 6(24): 467.
  2. Henriques BJ, Bross P, Gomes CM. Mutational hotspots in electron transfer flavoprotein underlie defective folding and function in multiple acyl-CoA dehydrogenase deficiency. Biochim Biophys Acta. 2010; 1802(11): 1070–1077.
  3. Olsen RKJ, Andresen BS, Christensen E, et al. Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. Hum Mutat. 2003; 22(1): 12–23.
  4. Taniguchi K, Kawai T, Hata K. Placental Development and Nutritional Environment. Adv Exp Med Biol. 2018; 1012: 63–73.
  5. Guibaud L, Collardeau-Frachon S, Lacalm A, et al. Antenatal manifestations of inborn errors of metabolism: prenatal imaging findings. J Inherit Metab Dis. 2017; 40(1): 103–112.
  6. Schulze A, Lindner M, Kohlmüller D, et al. Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications. Pediatrics. 2003; 111(6 Pt 1): 1399–1406.
  7. Olsen RKJ, Andresen BS, Christensen E, et al. DNA-based prenatal diagnosis for severe and variant forms of multiple acyl-CoA dehydrogenation deficiency. Prenat Diagn. 2005; 25(1): 60–64.
  8. Lehnert W, Wendel U, Lindenmaier S, et al. Multiple acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two brothers. I. Clinical, metabolical, and biochemical findings. Eur J Pediatr. 1982; 139(1): 56–59.
  9. Frerman FE, Goodman SI. Defects of electron transfer flavoprotein and electron transfer flavoprotein-ubiquinone oxidoreductase: glutaric acidemia type II. In: Scriver CR, Beaudet AL, Sly WS, Valle D. ed. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. McGraw-Hill Publishers, New York 2001.
  10. Indo Y, Glassberg R, Yokota I, et al. Molecular characterization of variant alpha-subunit of electron transfer flavoprotein in three patients with glutaric acidemia type II--and identification of glycine substitution for valine-157 in the sequence of the precursor, producing an unstable mature protein in a patient. Am J Hum Genet. 1991; 49(3): 575–580.
  11. Colombo I, Finocchiaro G, Garavaglia B, et al. Mutations and polymorphisms of the gene encoding the beta-subunit of the electron transfer flavoprotein in three patients with glutaric acidemia type II. Hum Mol Genet. 1994; 3(3): 429–435.
  12. Beard SE, Spector EB, Seltzer WK, et al. Mutations in electron transfer flavoprotein: ubiquinone oxidoreductase (ETF:QO) in glutaric acidemia type II. Clin Res. 1993; 41: 271A.
  13. Avni FE, Garel C, Cassart M, et al. Imaging and classification of congenital cystic renal diseases. AJR Am J Roentgenol. 2012; 198(5): 1004–1013.
  14. https://github.com/bcbio/bcbio-nextgen.
  15. Li H, Durbin R, Li H, et al. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14): 1754–1760.
  16. Poplin R, Ruano-Rubio V, DePristo M, et al. Scaling accurate genetic variant discovery to tens of thousands of samples. .
  17. McKenna A, Hanna M, Banks E, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20(9): 1297–1303.
  18. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010; 38(16): e164.
  19. Gambin T, Akdemir ZC, Yuan Bo, et al. Homozygous and hemizygous CNV detection from exome sequencing data in a Mendelian disease cohort. Nucleic Acids Res. 2017; 45(4): 1633–1648.
  20. Goodman SI, Gallegos DA, Pullin CJ, et al. Antenatal diagnosis of glutaric acidemia. Am J Hum Genet. 1980; 32(5): 695–699.
  21. Mitchell G, Saudubray JM, Benoit Y, et al. Antenatal diagnosis of glutaric aciduria type II. Lancet. 1983: 1099.
  22. Boué J, Chalmers RA, Tracey BM, et al. Prenatal diagnosis of dysmorphic neonatal-lethal type II glutaric aciduria. Lancet. 1984: 846–847.
  23. Bennett MJ, Curnock DA, Engel PC, et al. Glutaric aciduria type II: biochemical investigation and treatment of a child diagnosed prenatally. J Inherit Metab Dis. 1984; 7(2): 57–61.
  24. Henderson HE, Balla R, de Jo, et al. Postnatal and antenatal laboratory diagnosis of glutaric aciduria II in a South African family. S Afr Med J. 1987; 71: 589–591.
  25. Yamaguchi S, Shimizu N, Orii T, et al. Prenatal diagnosis and neonatal monitoring of a fetus with glutaric aciduria type II due to electron transfer flavoprotein (beta-subunit) deficiency. Pediatr Res. 1991; 30(5): 439–443.
  26. Sakuma T, Sugiyama N, Ichiki T, et al. Analysis of acylcarnitines in maternal urine for prenatal diagnosis of glutaric aciduria type 2. Prenat Diagn. 1991; 11(2): 77–82.
  27. Kjaergaard S, Graem N, Larsen T, et al. Recurrent fetal polycystic kidneys associated with glutaric aciduria type II. APMIS. 1998; 106(12): 1188–1193.
  28. Chisholm CA, Vavelidis F, Lovell MA, et al. Prenatal diagnosis of multiple acyl-CoA dehydrogenase deficiency: association with elevated alpha-fetoprotein and cystic renal changes. Prenat Diagn. 2001; 21(10): 856–859.
  29. Przyrembel H, Wendel U, Becker K, et al. Glutaric aciduria type II: report on a previously undescribed metabolic disorder. Clin Chim Acta. 1976; 66(2): 227–239.
  30. https://www.ncbi.nlm.nih.gov/gtr/conditions/C0268596/.
  31. Goodman SI. Prenatal diagnosis of glutaric acidemias. Prenat Diagn. 2001; 21(13): 1167–1168.
  32. Manning NJ, Bonham JR, Downing M, et al. Normal acylcarnitines in maternal urine during a pregnancy affected by glutaric aciduria type II. J Inherit Metab Dis. 1999; 22(1): 88–89.
  33. Łaczmańska I, Stembalska A. [New molecular methods in prenatal invasive diagnostics]. Ginekol Pol. 2013; 84(10): 871–876.
  34. Yates CL, Monaghan KG, Copenheaver D, et al. Whole-exome sequencing on deceased fetuses with ultrasound anomalies: expanding our knowledge of genetic disease during fetal development. Genet Med. 2017; 19(10): 1171–1178.
  35. Kosinski P, Ferreira JC, Lipa M, et al. Preferences and expectations among Polish women regarding prenatal screening. Ginekol Pol. 2019; 90(9): 544–548.